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Study flow diagram. HBV: hepatitis B virus; RCT: randomised clinical trial.
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Figure 1

Study flow diagram. HBV: hepatitis B virus; RCT: randomised clinical trial.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Trial sequential analysis of progression to chronic hepatitis B virus infection (lamivudine versus placebo or no treatment) and adverse events (proportion) (interferon versus placebo): Using the control group proportion observed in the trials (Pc = 41.3% and 34.9% respectively), alpha error of 2%, beta error of 90%, relative risk reduction (RRR) of 20%, and diversity observed in the analysis (0%), the accrued sample sizes (285 and 200 respectively) were only small proportions of the diversity‐adjusted required information sizes (DARIS) (progression to chronic hepatitis B = 1783; adverse events (proportion) = 2303). While the Z‐curve (blue lines) crossed the conventional boundary of P = 0.05 (dotted green lines) favouring placebo or no treatment, it did not cross any of the trial sequential monitoring boundaries (dotted red lines). There was a high risk of random errors.
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Figure 4

Trial sequential analysis of progression to chronic hepatitis B virus infection (lamivudine versus placebo or no treatment) and adverse events (proportion) (interferon versus placebo): Using the control group proportion observed in the trials (Pc = 41.3% and 34.9% respectively), alpha error of 2%, beta error of 90%, relative risk reduction (RRR) of 20%, and diversity observed in the analysis (0%), the accrued sample sizes (285 and 200 respectively) were only small proportions of the diversity‐adjusted required information sizes (DARIS) (progression to chronic hepatitis B = 1783; adverse events (proportion) = 2303). While the Z‐curve (blue lines) crossed the conventional boundary of P = 0.05 (dotted green lines) favouring placebo or no treatment, it did not cross any of the trial sequential monitoring boundaries (dotted red lines). There was a high risk of random errors.

Comparison 1 Pharmacological treatments for acute hepatitis B virus infection, Outcome 1 Mortality.
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Analysis 1.1

Comparison 1 Pharmacological treatments for acute hepatitis B virus infection, Outcome 1 Mortality.

Comparison 1 Pharmacological treatments for acute hepatitis B virus infection, Outcome 2 Chronic hepatitis B virus infection.
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Analysis 1.2

Comparison 1 Pharmacological treatments for acute hepatitis B virus infection, Outcome 2 Chronic hepatitis B virus infection.

Study

Number of events (intervention)

Number of participants (intervention)

Number of events (control)

Number of participants (control)

Interferon versus placebo

Tassopoulos 1989

0

67

0

33

Lamivudine versus placebo or no intervention

Kumar 2007

0

31

0

40

Streinu‐Cercel 2016

0

69

0

110

Lamivudine versus entecavir

Streinu‐Cercel 2016

0

69

0

21

Entecavir versus no intervention

Streinu‐Cercel 2016

0

21

0

110

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Analysis 1.3

Comparison 1 Pharmacological treatments for acute hepatitis B virus infection, Outcome 3 Serious adverse events.

Comparison 1 Pharmacological treatments for acute hepatitis B virus infection, Outcome 4 Adverse events proportion.
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Analysis 1.4

Comparison 1 Pharmacological treatments for acute hepatitis B virus infection, Outcome 4 Adverse events proportion.

Comparison 1 Pharmacological treatments for acute hepatitis B virus infection, Outcome 5 Adverse events number.
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Analysis 1.5

Comparison 1 Pharmacological treatments for acute hepatitis B virus infection, Outcome 5 Adverse events number.

Study

Mean (interferon)

Number of participants (interferon)

Mean (control)

Number of participants (control)

Mean difference

Statistical significance

Further details on scale used

Interferon versus placebo

Tassopoulos 1997

48.1

67

42.7

33

5.4

Not stated

Scale not stated. Not reported whether higher score indicates better or worse

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Analysis 1.6

Comparison 1 Pharmacological treatments for acute hepatitis B virus infection, Outcome 6 Health‐related quality of life.

Comparison 1 Pharmacological treatments for acute hepatitis B virus infection, Outcome 7 Seroconversion.
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Analysis 1.7

Comparison 1 Pharmacological treatments for acute hepatitis B virus infection, Outcome 7 Seroconversion.

Comparison 1 Pharmacological treatments for acute hepatitis B virus infection, Outcome 8 Time to seroconversion.
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Analysis 1.8

Comparison 1 Pharmacological treatments for acute hepatitis B virus infection, Outcome 8 Time to seroconversion.

Study

Mean (lamivudine)

Number of participants (lamivudine)

Mean (control)

Number of participants (control)

Mean difference

Statistical significance

Lamivudine versus placebo or no intervention

Wiegand 2014

17

18

16

17

1

P = 0.519 (not statistically significant)

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Analysis 1.9

Comparison 1 Pharmacological treatments for acute hepatitis B virus infection, Outcome 9 Time to seroconversion [weeks].

Summary of findings for the main comparison. Lamivudine versus no intervention for acute hepatitis B virus infection

Lamivudine versus no intervention for acute hepatitis B virus infection

Patient or population: people with acute HBV infection

Settings: secondary or tertiary care

Intervention: lamivudine

Control: no intervention

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(trials)

Quality of the evidence
(GRADE)

Assumed risk

Corresponding risk

No intervention

Lamivudine

Short‐term mortality (< 1 year)

33 per 1000

43 per 1000
(11 to 147)

OR 1.29
(0.33 to 4.99)

250
(2 trials)

⊕⊝⊝⊝
Very low1,2,3

Progression to chronic HBV infection (6 to 12 months)

413 per 1000

584 per 1000
(425 to 726)

OR 1.99
(1.05 to 3.77)

285
(3 trials)

⊕⊝⊝⊝
Very low1,2,3

Progression to fulminant HBV infection

None of the trials reported this information.

Serious adverse events (6 to 12 months)

There were no serious adverse events in either group.

250

(2 trials)

⊕⊝⊝⊝
Very low1,2,3

Adverse events (proportion) (12 months)

647 per 1000

722 per 1000
(384 to 916)

OR 1.42
(0.34 to 5.94)

35
(1 trial)

⊕⊝⊝⊝
Very low1,2,3

Adverse events (number of events) (12 months)

1235 per 1000

2124 per 1000
(1247 to 3594)

Rate ratio 1.72
(1.01 to 2.91)

35
(1 trial)

⊕⊝⊝⊝
very low1,2,3

Health‐related quality of life (1 week)

None of the trials reported this information.

*The basis for the assumed risk is the mean control group risk in the control group across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: confidence interval; HBV: hepatitis B virus; OR: odds ratio.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 The risk of bias in the trial(s) was high (downgraded by 1 level for risk of bias).
2 The sample size was small (downgraded by 1 level for imprecision)
3 The confidence intervals were wide (downgraded by 1 level for imprecision).

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Summary of findings for the main comparison. Lamivudine versus no intervention for acute hepatitis B virus infection
Summary of findings 2. Interferon versus no intervention for acute hepatitis B virus infection

Interferon versus no intervention for acute hepatitis B virus infection

Patient or population: people with acute HBV infection

Settings: secondary or tertiary care

Intervention: interferon

Control: no intervention

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(trials)

Quality of the evidence
(GRADE)

Assumed risk

Corresponding risk

No intervention

Interferon

Short‐term mortality

None of the trials reported this information.

Progression to chronic HBV infection

None of the trials reported this information.

Progression to fulminant HBV infection

None of the trials reported this information.

Serious adverse events

There were no serious adverse events in either group.

100

(1 trial)

⊕⊝⊝⊝
Very low1,2,3

Adverse events (proportion) (4 to 6 months)

273 per 1000

992 per 1000
(945 to 999)

OR 348.16
(45.39 to 2670.26)

200
(2 trials)

⊕⊕⊝⊝
Low1,2

Adverse events (number of events)

None of the trials reported this information.

Health‐related quality of life (1 week)

The scale used to report the health‐related quality of life was not stated. Neither was information on whether higher score meant better or worse available. The mean score in the placebo group was 42.7 units. The mean score in the interferon group was 5.4 units higher. There was no information to calculate the 95% confidence intervals or P value.

100
(1 trial)

⊕⊝⊝⊝
Very low1,2,3

*The basis for the assumed risk is the mean control group risk in the control group across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: confidence interval; HBV: hepatitis B virus; OR: odds ratio.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 The risk of bias in the trial(s) was high (downgraded by 1 level for risk of bias).
2 The sample size was small (downgraded by 1 level for imprecision).
3 The confidence intervals were wide (downgraded by 1 level for imprecision).

Figures and Tables -
Summary of findings 2. Interferon versus no intervention for acute hepatitis B virus infection
Table 1. Characteristics of included studies arranged according to comparison

Study name

Intervention

Control

Follow‐up period (months)

Sequence generation

Allocation concealment

Blinding of participants and healthcare providers

Blinding of outcome assessors

Incomplete outcome data

Selective outcome reporting

Source of funding

Other bias

Overall risk of bias

Anonymous 1974

Hepatitis B Immunoglobulin

Placebo

Not stated

Low

Low

Unclear

Unclear

Unclear

High

Low

Low

High

Tassopoulos 1989

Interferon

Placebo

Min 5

Unclear

Unclear

Unclear

Unclear

Unclear

High

High

Low

High

Tassopoulos 1997

Interferon

Placebo

Min 5

Unclear

Unclear

Low

Low

Low

High

High

Low

High

Apostolescu 2001

Lamivudine

No intervention

Min 3

Unclear

Unclear

Unclear

Unclear

Unclear

High

Unclear

Low

High

Kumar 2007

Lamivudine

Placebo

Min 12

Low

Unclear

Low

Low

Low

Low

Unclear

Low

Unclear

Wiegand 2014

Lamivudine

Placebo

Not stated

Unclear

Unclear

Unclear

Unclear

High

High

Low

Low

High

Streinu‐Cercel 2016

Lamivudine

Control 1: entecavir
Control 2: no intervention

Min 11

Low

Unclear

High

High

Low

High

Low

Low

High

Min: minimum.

Figures and Tables -
Table 1. Characteristics of included studies arranged according to comparison
Comparison 1. Pharmacological treatments for acute hepatitis B virus infection

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Mortality Show forest plot

3

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

1.1 Hepatitis B immunoglobulin (HBIG) versus placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

1.2 Lamivudine versus placebo or no intervention

2

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

1.3 Lamivudine versus entecavir

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

1.4 Entecavir versus no intervention

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2 Chronic hepatitis B virus infection Show forest plot

3

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

2.1 Lamivudine versus placebo or no intervention

3

285

Odds Ratio (M‐H, Fixed, 95% CI)

1.99 [1.05, 3.77]

2.2 Lamivudine versus entecavir

1

90

Odds Ratio (M‐H, Fixed, 95% CI)

3.64 [1.31, 10.13]

2.3 Entecavir versus no intervention

1

131

Odds Ratio (M‐H, Fixed, 95% CI)

0.58 [0.23, 1.49]

3 Serious adverse events Show forest plot

Other data

No numeric data

3.1 Interferon versus placebo

Other data

No numeric data

3.2 Lamivudine versus placebo or no intervention

Other data

No numeric data

3.3 Lamivudine versus entecavir

Other data

No numeric data

3.4 Entecavir versus no intervention

Other data

No numeric data

4 Adverse events proportion Show forest plot

3

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

4.1 Interferon versus placebo

2

200

Odds Ratio (M‐H, Fixed, 95% CI)

348.16 [45.39, 2670.26]

4.2 Lamivudine versus placebo or no intervention

1

35

Odds Ratio (M‐H, Fixed, 95% CI)

1.42 [0.34, 5.94]

5 Adverse events number Show forest plot

1

Rate Ratio (Fixed, 95% CI)

Totals not selected

5.1 Lamivudine versus placebo or no intervention

1

Rate Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

6 Health‐related quality of life Show forest plot

Other data

No numeric data

6.1 Interferon versus placebo

Other data

No numeric data

7 Seroconversion Show forest plot

5

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

7.1 Interferon versus placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7.2 Lamivudine versus placebo or no intervention

4

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7.3 Lamivudine versus entecavir

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7.4 Entecavir versus no intervention

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

8 Time to seroconversion Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

8.1 Interferon versus placebo

1

Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

9 Time to seroconversion [weeks] Show forest plot

Other data

No numeric data

9.1 Lamivudine versus placebo or no intervention

Other data

No numeric data

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Comparison 1. Pharmacological treatments for acute hepatitis B virus infection